Administration of either fluorouracil (FUra) by protracted infusion or bolus FUra modulated by leucovorin results in response rates of 20%-30% in patients with advanced colorectal cancer is 10-11 months. thus, innovative strategies are crucially needed to improve the prognosis of patients with colorectal cancer and other adenocarcinomas arising in the gastrointestinal tract. We are taking several approaches. First, we are trying to improve the activity of 5-FU/leucovorin in clinical trials through the addition of other modulatory agents such as interferon alpha and gamma, and to reduce the toxicity with GM-CSF and alteration of the FUra infusion duration. We are also studying the interaction of other agents with FUra in the laboratory in an effort to define optimal doses and sequences of drug combinations for potential clinical use. In addition, we believe the identification of new agents with potential activity against adenocarcinomas of the gastrointestinal tract is of paramount importance. We are particularly interested in new drugs which display potent in vitro activity (IC50 for a 24 hour exposure less than or equal to 10 mu M) and/or in vivo efficacy against human colorectal carcinoma cell lines. Studies designed to elucidate the optimal schedule of administration and mechanism of action of such agents are vital to facilitate their rational clinical use. We have continuing interest in the implementation of Phase I clinical trials which incorporate biochemical or molecular endpoints as a reflection of the biologic activity of the particular agent. Our ultimate goal is to develop new agents and drug combinations which may be useful in the treatment of patients with malignancies arising in the gastrointestinal tract. These therapeutic strategies may also have application in the treatment of other epithelial solid tumors including breast cancer and head and neck cancer.